Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/38—Cellulose; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• Eosinophilic esophagitis is a chronic immune/antigen-mediated disorder of the esophagus characterized histologically by eosinophil-predominant mucosal inflammation and clinically by symptoms of esophageal dysfunction. Its incidence in children has been increasing and is currently similar to that of pediatric inflammatory bowel disease (IBD). EoE involves progressive esophageal remodeling that can lead to esophageal dysmotility and strictures, if untreated. Therapeutic targets currently include improvement of symptoms, remission of histopathological features and prevention of long-term complications ( Oliva et al., Digestive Diseases and Sciences (2019), 64; 1571-1578 ).
• Topical corticosteroids predominantly fluticasone and budesonide, are considered the most effective first-line treatment as well as an option for maintenance therapy in EoE. These drugs induce histological remission, lead to the resolution of clinical symptoms and prevent fibrosis.
• budesonide orodispersible tablets i.e. Jorveza ®
• MDI metered-dose inhalers
• EP 3 834 819 describes the treatment of a six-year old male patient with oral prednisone and the treatment of a five-year old girl with Pulmicort ® mixed with sucralose.
• EoE is a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation exclusively in the esophageal mucosa.
• the disease affects not only adults but also young children with 1 year up to 18 years and adolescents.
• the major challenge of the treatment of EoE is the identification and selection of a suitable dosage form that considers the physico-chemical characteristics of the active pharmaceutical ingredient and that facilitates its delivery to the affected areas of the esophagus after oral administration to ensure topical treatment, i.e. the drug product should be orally applied but locally acting in the esophagus. While these attributes of the dosage form are age-independent and apply to the entire patient population, there are special and critical features that are unique to the pediatric patient population. The general and critical features or quality attributes require the selection of a suitable age-appropriate pediatric dosage form providing the following characteristics:
• Budesonide is a potent glucocorticosteroid with a high topical anti-inflammatory activity and with low systemic effects. It has been widely used as active pharmaceutical ingredient for the treatment of asthma or inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. In addition, it is also used to treat EoE in adults.
• liquid and solid formulations are generally considered as the first choice when selecting an age-appropriate pediatric dosage form for oral administration.
• budesonide tends to be susceptible to chemical degradation in liquid and semi-solid formulations especially when not sufficiently stabilized. This strongly limits the number of potential age-appropriate pediatric dosage forms of budesonide. Therefore, and opposed to adults, children are currently excluded from a suitable treatment of eosinophilic esophagitis with a budesonide-containing drug product meeting all the required features.
• the major challenge of the development was the identification and selection of a suitable age-appropriate pediatric dosage form considering the physico-chemical properties of budesonide and meeting the core enabling criteria for appropriateness such as acceptability, dosing flexibility, esophagus targeting, biopharmaceutical fitness, sustainability and commercial viability.
• solid dosage forms are generally preferred over liquid dosage forms.
• Potential formulations are powders and granules, tablets or minitablets, orodispersible tablets, chewable or effervescent tablets and capsules. When administered to children, however, all these formulations will quickly pass the esophagus after swallowing and deliver budesonide predominantly into the stomach. Esophagus targeting, the essential criterion for the selection of a suitable dosage form to treat eosinophilic esophagitis will not be achieved in the target pediatric population.
• the especially preferred age-appropriate pediatric dosage form to target the esophagus is a highly viscous aqueous suspension of budesonide in a concentration of about 0.2 mg/mL that is presented in a 200 mL amber glass bottle (type III glass) as multi-dose container with a child-resistant closure (white LDPE screw cap with an internal colorless LDPE flow limiter).
• the required doses are withdrawn from the bottle using a suitable measuring device (i.e. oral syringe) that also allows flexible dosing.
• the flow limiter remains in the bottle neck and enables the insertion of the oral syringe for withdrawal of the suspension.
• the drug product is stable under long-term storage conditions and provides a sufficiently long in-use stability after first opening.
• an oral suspension comprises the suspended active pharmaceutical ingredient with defined characteristics in terms of crystallinity and particle size distribution, the viscosity-increasing agent that affects the physical stability of the formulation and the components of the outer phase of the suspension affecting the chemical stability, preservation, organoleptic properties and safety of the formulation.
• the invention comprises an aqueous oral suspension of the active pharmaceutical ingredient budesonide which is per se practically insoluble in water. As the vehicle is already saturated with dissolved budesonide, the undissolved drug particles are immediately available for dissolution after delivery to the esophagus.
• the present invention in its broadest sense relates to an orally applicable suspension comprising the following components:
• a topically acting micronized crystalline glucocorticosteroide for the present invention is budesonide.
• the orally applicable suspension is aqueous.
• the main component is therefore purified water which can be used for pharmaceutical purposes.
• Another very important component is a viscosity-increasing agent which is in the present case selected from methylcellulose or a derivative thereof.
• the methylcellulose preferably used in the present invention is a methyl ester of cellulose that contains about 20-50% of methoxy groups. Methylcellulose is soluble in water and a wide range of viscosity grades can be obtained depending on the average molecular weight range which is between 10000 and 220000 Da. Depending on the particular type of methylcellulose the amount required for obtaining a dynamic viscosity in the range of 800 mPa*s to 2000 mPa*s is added. The amount of the methylcellulose which is added to the solution is preferably less than 2% weight/weight.
• the viscosity is influenced by the length of the cellulose chain and the degree of methylation.
• Methylcellulose is a nonionic water-soluble cellulose ether where some of the hydroxy groups of cellulose are substituted with methyl groups leading to methoxy groups. It is a pharmacopoeial excipient and described in the European Pharmacopoeia (Ph. Eur.), the Pharmacopoeia of the United States (USP) and other Pharmacopoeias. As partly O-methylated cellulose the content of methyl groups ranges from 26.0 per cent to 33.0 per cent. The average degree of substitution is 1.5 ranging from 1.4 to 2.0 so that on average one glucopyranose unit contains 1.5 methoxy groups.
• Methylcellulose is a polymer comprising numerous linked glucopyranose units with a mean chain length of 200 to 1000 and relative molecular weights of 20,000 to 150,000.
• the viscosity of methylcellulose solutions is related to the concentration and molecular weight of the polymer.
• Methylcellulose dissolves in cold water giving a colloidal solution. Despite its insolubility in hot water, the hot water method is preferably used to prepare the colloidal solutions. After dispersing and wetting the polymer in hot water, the mixture is cooled down so that complete dissolution can be achieved that results in a clear solution.
• the invented budesonide 0.2 mg/mL oral suspension is preferably manufactured using methylcellulose grade 1500 mPa*s at a concentration of 20 mg/mL. However, adjustment of the visocsity can also be accomplished with other methylcellulose grades or with combinations or blends of different methylcellulose grades. Thus the preferred target viscosity of 1000 mPa*s (within the range of 800 to 1200 mP*s) of the drug product can be reliably adjusted.
• methylcelluloses are usually used in the oral application suspension in a range from 10 mg/ml to 50 mg/ml, preferably 15 mg/ml to 25 mg/ml and most preferred 20 mg/ml.
• the orally applicable suspension must have a well-defined pH value whereby two aspects have to be observed. On the one hand the pH must be in a range where the suspended budesonide is highly stable and on the other hand the pH must be in a range which is well accepted when the suspension is applied to the patient.
• Many buffers used for pharmaceutical formulations are systems comprising carbonates, citrates, tartrates and various phosphate salts. In the present case a citrate buffering system is especially preferred.
• the orally applicable suspension also contains preservatives which prevent the growth of undesired microorganisms like bacteria or fungi in the suspension once it is opened for the first time.
• preservatives which prevent the growth of undesired microorganisms like bacteria or fungi in the suspension once it is opened for the first time.
• a preservative is used in the present case which is well tolerable for the target patient group.
• Suitable antimicrobial preservatives for oral liquid formulations are sorbic acid or its potassium salt, benzoic acid or its sodium salt, parahydroxybenzoate esters (especially methyl and ethyl) or their sodium salts and ethanol. They are used alone or in combinations.
• the selection of a suitable antimicrobial preservative or combination of preservatives should be carefully conducted when used in pediatric formulations. In particular preferred is sodium benzoate.
• the dissolved and undissolved budesonide are stabilized by adjusting the pH value of the aqueous continuous external phase to 3.5 to 4.5 and by adding the disodium salt of ethylenediaminetetraacetic acid (EDTA) as stabilizer to the outer phase. Under these conditions the chemical and microbiological long-term stability of the suspension can be ensured.
• EDTA ethylenediaminetetraacetic acid
• the orally applicable suspension has an appropriate viscosity.
• the viscosity is measured according to the methods as described in the European Pharmacopeia [2.2.10].
• the viscosity ranges from 500 mPa*s to 2000 mPa*s, preferably from 800 mPa*s to 1200 mPa*s and particularly preferred to about 1000 mPa*s.
• the concentration of the glucocorticosteroid is in the range of about 0.1-1.0 mg/ml budesonide. Particularly preferred ranges are from 0.1-0.5 mg/ml whereby 0.2 mg/ml is particularly preferred.
• the pharmaceutically active agents are applied in a micronized form.
• This is a particular treatment of the budesonide whereby at least 95% of the budesonide microparticles have a diameter of less than 10 ⁇ m.
• Particularly preferred is that at least 95% of the budesonide microparticles have a diameter of less than 5 ⁇ m.
• the viscosity is in a range of 1000-15000 mPa*s and especially preferred is a viscosity of about 1200 mPa*s whereby the viscosity is dependent on the type of methylcellulose and not on the amount of viscosity enhancer.
• the orally applicable suspension contains a flavoring agent whereby cassis aroma is particularly preferred.
• the orally applicable suspension is to be applied to children it contains no surfactant and it contains no antioxidant. This can advantageously increase the willingness of patients or their caregivers to take medication with the orally applicable suspension according to the invention.
• the orally applicable suspensions according to the invention contain no other viscosity-increasing agent except methylcellulose or derivatives thereof as described above. Different types of methylcellulose as described above can be mixed.
• the orally applicable suspension according to the present invention is intended for use in the treatment of eosinophilic esophagitis in children who are patients having an age from about 1 to 2 years to about 17 years.
• the amount of the glucocorticosteroid, in particular the budesonide is 0.5 to 1 mg per dose which is administered in an amount of 2.5-5 ml suspension depending on the concentration of the orally applicable suspension.
• Such dose is applied preferably twice a day, namely one dose in the morning and one dose in the evening.
• the orally applicable suspension according to the invention is prepared in a special process whereby in a first process step an aqueous base is mixed with the viscosity-increasing agent producing a first suspension without the pharmaceutically active agent.
• the solution is usually produced by temperature treatment which means that the solution is slightly heated.
• an aqueous solution containing a buffering agent, an antimicrobial preservative and a suspension stabilizing agent is prepared.
• a third step the solution containing the viscosity-increasing agent obtained from step 1 is mixed with the solution containing the buffering agent, an antimicrobial preservative and a suspension stabilizing agent and in a fourth step the micronized corticosteroid is suspended under stirring in the solution as described above. Finally, the flavoring agent is added before the budesonide solution is filled into light protected bottles.
• the preparation of the solution must be prepared by observing the strictest standards of good manufacturing practice for preparing syrups.
• FIG. 1 A scheme for the preparation of an orally applicable suspension according to the invention is shown in Fig. 1 .
• the preferred suspending and thickening agent of the invention is methylcellulose.
• Other pharmaceutically acceptable, inert and mucoadhesive nonionic cellulose derivatives could be used as suspending and thickening agent as minor component.
• Minor component means that such a component is present in an amount not exceeding 1 mg/ml, preferably not exceeding 0.5 mg/ml of the final orally applicable suspension.
• the advantage of methylcellulose is that the viscosity can be adjusted independently of the pH value. Thus, the viscosity can or is preferably adjusted at an acidic pH value, in particular in a range of pH 3.5 to 4.5. Moreover, it is of utmost importance that the solution when used by the patient sticks to the esophagus of the patient for sufficient time to develop its effect.
• the orally applicable solution according to the invention sticks very well to patient's esophagus and it does not cause an uncomfortable feeling.
• Budesonide 0.2 mg/mL oral suspension is a whitish, highly viscous suspension with a characteristic cassis flavor.
• One bottle of the 200 ml amber glass bottle contains > 160 ml of the liquid preparation.
• the drug product is usually manufactured in batches of approximately 434 kg resulting in 2500 bottles with a filling volume of 165 ml.
• the qualitative and quantitative composition of the invention per mL of the suspension, per dose of 5 mL and per batch of 434 kg are presented below.
• Table 1 shows a preferred composition of the orally applicable solution according to the invention.
• Table 1 Component Qualitative and quantitative composition [mg/mL] [mg/5 ml] [kg/batch]
• Budesonide 0.20 1.00 0.08250 Sucrose 100.00 500.00 41.2500
• Sodium benzoate 0.86 4.30 0.35475 Disodium edetate 1.00 5.00 0.41250 Citric acid, anhydrous 0.70 3.50 0.28875 Methylcellulose 20.00 100.00 8.25000
• the manufacturing process of budesonide 0.2 mg/mL oral suspension comprises the process steps to prepare the bulk suspension and the filling process.
• the flow chart as shown in Fig. 1 describes the manufacturing process of the bulk suspension (batch size 434.115 kg).
• the described invention has been successfully tested in children in clinical studies.
• Several drug product batches were manufactured to supply the clinical trials. All the tested batches had the invented qualitative and quantitative composition as described above using methylcellulose, 1500 mPa*s with a concentration of 20 mg/ml (equivalent to 1.90%).
• the measured dynamic viscosity of the clinical batches is presented below (method: rotating viscosity according to Ph. Eur.
• the specific viscosity values were obtained by using appropriate amounts of methylcellulose having 1500 mPa*s.
• Table 2 A comparison between the two dosing schemes is shown in Table 2.
• the study using the suspension described herein is a similar study to a study assessing efficacy and safety of an oral budesonide suspension in a comparable paediatric patient population suffering EoE.
• GUPTA et al. Clinical Gastroenterol. and Hepatol. 2015, vol. 13, No. 1, pp 66-67 .
• a dose of 1.4 and 2.0 mg was given in a 7 ml and 10 ml volume either in a once daily or in a twice daily dosing regimen.
• efficacy was analysed by measuring the number of eosinophils per hpf.
• Histological response was defined as eos ⁇ 6 per hpf, histological remission as eos ⁇ 1 per hpf (see Table 3).
• Table 3 Gupta Treatment regimen OD BID Daily dose 1.4 - 2.0 mg 2.8 - 4.0 mg Volume 1 ⁇ 7 ml (2-9 y.) 2 ⁇ 7 ml (2-9 y.) 1 ⁇ 10 ml (10-18 y.) 2 ⁇ 10 ml (10-18 y.) Eos ⁇ 6 per hpf 52.6 % 94.1 % Eos ⁇ 1 per hpf 42.1 % 76.5 %
• budesonide is stable against degradation when it is not in an aqueous environment. In solution or suspension, however, budesonide may be degraded which leads to undesired degradation products of budesonide which are not more highly pharmacologically active.

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